The antiobesity agent fenfluramine (meta-trifluoromethyl N-ethylamphetamine) may be less subject to human abuse than amphetamine of N-ethylamphetamine (NEA) since fenfluramine is not a reinforcer of self-injection responding, of a locomotor-stimulant in animals. Studies using a series of meta-substituted NEAs indicate that the behavioral potencies of the NEAs are related to norepinephrine (NE) release, that drug entry through the noradrenergic neuronal membrane is limited by meta-substituent bulk and suggest that the noradrenergic uptake carrier is the bulk-sensitive site. The neurochemical basis for the inverse bulk-efficacy relationship is less clear but may involve release of NE, dopamine and serotonin (5HT) and epinephrine (EPI). NEA is a "low bulk" drug and its ability to release NE (and perhaps EPI) both in vivo and vitro as well as its ability to stimulate locomotion (but not stereotypy) in mice are antagonized by NE uptake inhibitors. This is in contrast to the effects of neuroleptics which selectively inhibit stereotypy. Fenfluramine apparently stimulates locomotor activity in monoamine oxidase inhibited mice, and monoamine oxidase inhibition potentiates fenfluramine-induced release of NE, dopamine and 5HT. Since these and other observations suggest that similar neurochemical bases underlie drug-induced locomotor activity, and the reinforcing and euphorigenic effects of such drugs, the proposed studies will evaluate 1) the ability of inhibitors of NE uptake to act as antagonists of the reinforcing and euphorigenic effects of amphetamine and its congeners in species in which these inhibitors do not antagonize the metabolism of such drugs: mouse, and through collaboration, rhesus monkey and man, 2) the effects of acute and chronic NE uptake inhibition and neuroleptic administration on amphetamine-induced mouse locomotor activity, stereotypy and neurochemical alterations 3) the effects of pargyline on response-contingent presentations or terminations of fenfluramine infusions in the mouse and 4) the interaction of amphetamine and central EPI behaviorally and biochemically using selective inhibitors of EPI synthesis and uptake, as well as the neurotoxin 6-hydroxydopamine.